Aqueous Pharmaceutical Formulations of ER-beta Selective Ligands

Abstract

The present invention relates to aqueous formulations of ERβ selective ligands. In some embodiments, the formulations include an ERβ selective ligand, a solubilizer/complexant component, and a pH adjusting component. The invention further provides preparations of the formulations, and uses thereof.

1 . An aqueous pharmaceutical composition comprising:
 a) an ERβ selective ligand in an amount of from about 0.14 μg/mL to about 40 mg/mL;   b) a solubilizer/complexant component comprising from about 0.00021% (w/v) to about 60% (w/v) of the pharmaceutical composition; and   c) an optional pH adjusting component in a concentration of from about 8.75×10 −7  N to about 1.0 N;   wherein the ERβ selective ligand has the Formula I:   
     
       
         
         
             
             
         
       
     
     wherein:
 R 1  is hydrogen, hydroxyl, halogen, alkyl of 1-6 carbon atoms, trifluoroalkyl of 1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, alkoxy of 1-6 carbon atoms, trifluoroalkoxy of 1-6 carbon atoms, thioalkyl of 1-6 carbon atoms, sulfoxoalkyl of 1-6 carbon atoms, sulfonoalkyl of 1-6 carbon atoms, aryl of 6-10 carbon atoms, a 5 or 6-membered heterocyclic ring having 1 to 4 heteroatoms selected from O, N or S, —NO 2 , —NR 5 R 6 , —N(R 5 )COR 6 , —CN, —CHFCN, —CF 2 CN, alkynyl of 2-7 carbon atoms, or alkenyl of 2-7 carbon atoms; wherein the alkyl or alkenyl moieties are optionally substituted with hydroxyl, —CN, halogen, trifluoroalkyl, trifluoroalkoxy, —COR 5 , —CO 2 R 5 , —NO 2 , CONR 5 R 6 , NR 5 R 6  or N(R 5 )COR 6 ; 
 R 2  and R 2a  are each, independently, hydrogen, hydroxyl, halogen, alkyl of 1-6 carbon atoms, alkoxy of 1-4 carbon atoms, alkenyl of 2-7 carbon atoms, or alkynyl of 2-7 carbon atoms, trifluoroalkyl of 1-6 carbon atoms, or trifluoroalkoxy of 1-6 carbon atoms; wherein the alkyl or alkenyl moieties are optionally substituted with hydroxyl, —CN, halogen, trifluoroalkyl, trifluoroalkoxy, —COR 5 , —CO 2 R 5 , —NO 2 , CONR 5 R 6 , NR 5 R 6  or N(R 5 )COR 6 ; 
 R 3 , R 3ax, and R   4  are each, independently, hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, halogen, alkoxy of 1-4 carbon atoms, trifluoroalkyl of 1-6 carbon atoms, or trifluoroalkoxy of 1-6 carbon atoms; wherein the alkyl or alkenyl moieties are optionally substituted with hydroxyl, —CN, halogen, trifluoroalkyl, trifluoroalkoxy, —COR 5 , —CO 2 R 5 , —NO 2 , CONR 5 R 6 , NR 5 R 6  or N(R 5 )COR 6 ; 
 R 5 , R 6  are each, independently, hydrogen, alkyl of 1-6 carbon atoms, aryl of 6-10 carbon atoms; 
 X is O, S, or NR 7 ; and 
 R 7  is hydrogen, alkyl of 1-6 carbon atoms, aryl of 6-10 carbon atoms, —COR 5 , —CO 2 R 5  or —SO 2 R 5 ; 
 or a pharmaceutically acceptable salt thereof; 
 or the Formula III: 
 
     
       
         
         
             
             
         
       
     
     wherein:
 R 11 , R 12 , R 13 , and R 14  are each, independently, selected from hydrogen, hydroxyl, alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, or halogen; 
 R 15 , R 16 , R 17 , R 18 , R 19 , and R 20  are each, independently, hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, halogen, alkoxy of 1-6 carbon atoms, —CN, —CHO, phenyl, or a 5 or 6-membered heterocyclic ring having 1 to 4 heteroatoms selected from O, N or S; wherein the alkyl or alkenyl moieties of R 15 , R 16 , R 17 , R 18 , R 19 , or R 20  may be optionally substituted with hydroxyl, CN, halogen, trifluoroalkyl, trifluoroalkoxy, NO 2 , or phenyl; wherein the phenyl moiety of R 15 , R 16 , R 17 , R 18 , R 19 , or R 20  may be optionally mono-, di-, or tri-substituted with alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, halogen, hydroxyl, alkoxy of 1-6 carbon atoms, CN, —NO 2 , amino, alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms per alkyl group, thio, alkylthio of 1-6 carbon atoms, alkylsulfinyl of 1-6 carbon atoms, alkylsulfonyl of 1-6 carbon atoms, alkoxycarbonyl of 2-7 carbon atoms, alkylcarbonyl of 2-7 carbon atoms, or benzoyl; and 
 wherein at least one of R 11 , R 12 , R 13 , R 14 , R 17 , R 18 , R 19  or R 20  is hydroxyl, or a pharmaceutically acceptable salt thereof. 
 
   
   
       2 . The pharmaceutical composition of  claim 1 , wherein:
 said ERβ selective ligand is present in an amount of from about 0.14 μg/mL to about 10 mg/mL;   said solubilizer/complexant component comprises from about 0.00021% (w/v) to about 15% (w/v) of the pharmaceutical composition; and   said optional pH adjusting component in an amount of about 8.75×10 −7  N to about 0.0625 N.   
   
   
       3 . The pharmaceutical composition of  claim 1 , wherein:
 said ERβ selective ligand is present in an amount of from about 1 mg/mL to about 40 mg/mL; and   said solubilizer/complexant component is present in an amount of from about 1% (w/v) to about 60% (w/v) of the pharmaceutical composition.   
   
   
       4 . The pharmaceutical composition of  claim 1 , wherein:
 said ERβ selective ligand is present in an amount of from about 5 mg/mL to about 40 mg/mL; and   said solubilizer/complexant component is present in an amount of from about 5% (w/v) to about 60% (w/v) of the pharmaceutical composition.   
   
   
       5 . The pharmaceutical composition of  claim 1 , wherein:
 said ERβ selective ligand is present in an amount of from about 1 mg/mL to about 10 mg/mL;   said solubilizer/complexant component is present in an amount of from about 1% (w/v) to about 15% (w/v) of the pharmaceutical composition; and   said optional pH adjusting component in an amount of about 8.75×10 −7  N to about 0.0625 N.   
   
   
       6 . The pharmaceutical composition of  claim 1 , wherein:
 said ERβ selective ligand is present in an amount of from about 5 mg/mL to about 10 mg/mL;   said solubilizer/complexant component is present in an amount of from about 5% (w/v) to about 15% (w/v) of the pharmaceutical composition; and   said optional pH adjusting component in an amount of about 8.75×10 −7  N to about 0.0625 N.   
   
   
       7 . The pharmaceutical composition of  claim 1 , wherein the ERβ selective ligand has the Formula II: 
     
       
         
         
             
             
         
       
     
     wherein:
 R 1  is alkenyl of 2-7 carbon atoms; wherein the alkenyl moiety is optionally substituted with hydroxyl, —CN, halogen, trifluoroalkyl, trifluoroalkoxy, —COR 5 , —CO 2 R 5 , —NO 2 , CONR 5 R 6 , NR 5 R 6  or N(R 5 )COR 6 ; 
 R 2  and R 2a  are each, independently, hydrogen, hydroxyl, halogen, alkyl of 1-6 carbon atoms, alkoxy of 1-4 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, trifluoroalkyl of 1-6 carbon atoms, or trifluoroalkoxy of 1-6 carbon atoms; wherein the alkyl, alkenyl, or alkynyl moieties are optionally substituted with hydroxyl, —CN, halogen, trifluoroalkyl, trifluoroalkoxy, —COR 5 , —CO 2 R 5 , —NO 2 , CONR 5 R 6 , NR 5 R 6  or N(R 5 )COR 6 ; 
 R 3 , and R 3a  are each, independently, hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, halogen, alkoxy of 1-4 carbon atoms, trifluoroalkyl of 1-6 carbon atoms, or trifluoroalkoxy of 1-6 carbon atoms; wherein the alkyl, alkenyl, or alkynyl moieties are optionally substituted with hydroxyl, —CN, halogen, trifluoroalkyl, trifluoroalkoxy, —COR 5 , —CO 2 R 5 , —NO 2 , CONR 5 R 6 , NR 5 R 6  or N(R 5 )COR 6 ; 
 R 5 , R 6  are each, independently, hydrogen, alkyl of 1-6 carbon atoms, aryl of 6-10 carbon atoms; 
 X is O, S, or NR 7 ; and 
 R 7  is hydrogen, alkyl of 1-6 carbon atoms, aryl of 6-10 carbon atoms, —COR 5 , —CO 2 R 5  or —SO 2 R 5 ; 
 or a pharmaceutically acceptable salt thereof. 
 
   
   
       8 . The pharmaceutical composition of  claim 7 , wherein the ERβ selective ligand has the Formula II, wherein X is O, and R 1  is alkenyl of 2-3 carbon atoms, which is optionally substituted with hydroxyl, —CN, halogen, trifluoroalkyl, trifluoroalkoxy, —COR 5 , —CO 2 R 5 , —NO 2 , CONR 5 R 6 , NR 5 R 6  or N(R 5 )COR 6 . 
   
   
       9 . The pharmaceutical composition of  claim 2 , wherein the ERβ selective ligand has the Formula II: 
     
       
         
         
             
             
         
       
     
     wherein:
 R 1  is alkenyl of 2-7 carbon atoms; wherein the alkenyl moiety is optionally substituted with hydroxyl, —CN, halogen, trifluoroalkyl, trifluoroalkoxy, —COR 5 , —CO 2 R 5 , —NO 2 , CONR 5 R 6 , NR 5 R 6  or N(R 5 )COR 6 ; 
 R 2  and R 2a  are each, independently, hydrogen, hydroxyl, halogen, alkyl of 1-6 carbon atoms, alkoxy of 1-4 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, trifluoroalkyl of 1-6 carbon atoms, or trifluoroalkoxy of 1-6 carbon atoms; wherein the alkyl, alkenyl, or alkynyl moieties are optionally substituted with hydroxyl, —CN, halogen, trifluoroalkyl, trifluoroalkoxy, —COR 5 , —CO 2 R 5 , —NO 2 , CONR 5 R 6 , NR 5 R 6  or N(R 5 )COR 6 ; 
 R 3 , and R 3a  are each, independently, hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, halogen, alkoxy of 1-4 carbon atoms, trifluoroalkyl of 1-6 carbon atoms, or trifluoroalkoxy of 1-6 carbon atoms; wherein the alkyl, alkenyl, or alkynyl moieties are optionally substituted with hydroxyl, —CN, halogen, trifluoroalkyl, trifluoroalkoxy, —COR 5 , —CO 2 R 5 , —NO 2 , CONR 5 R 6 , NR 5 R 6  or N(R 5 )COR 6 ; 
 R 5 , R 6  are each, independently, hydrogen, alkyl of 1-6 carbon atoms, aryl of 6-10 carbon atoms; 
 X is O, S, or NR 7 ; and 
 R 7  is hydrogen, alkyl of 1-6 carbon atoms, aryl of 6-10 carbon atoms, —COR 5 , —CO 2 R 5  or —SO 2 R 5 ; 
 or a pharmaceutically acceptable salt thereof. 
 
   
   
       10 . The pharmaceutical composition of  claim 1 , wherein the ERβ selective ligand has the Formula: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof. 
   
   
       11 . The pharmaceutical composition of  claim 10 , wherein the solubilizer/complexant component is selected from the group consisting of hydroxypropyl beta-cyclodextrin and sulfobutyl ether beta-cyclodextrin. 
   
   
       12 . The pharmaceutical composition of  claim 10 , wherein the solubilizer/complexant component comprises hydroxypropyl beta-cyclodextrin. 
   
   
       13 . The pharmaceutical composition of  claim 10 , wherein the pH adjusting component is selected from the group consisting of group I and group II metal hydroxides. 
   
   
       14 . The pharmaceutical composition of  claim 10 , wherein the pH adjusting component is selected from the group consisting of NaOH and KOH. 
   
   
       15 . The pharmaceutical composition of  claim 10 , wherein:
 the solubilizer/complexant component is selected from the group consisting of hydroxypropyl beta-cyclodextrin and sulfobutyl ether beta-cyclodextrin; and   the pH adjusting component is selected from the group consisting of group I and group II metal hydroxides.   
   
   
       16 . The pharmaceutical composition of  claim 2 , wherein the ERβ selective ligand has the Formula: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof. 
   
   
       17 . The pharmaceutical composition of  claim 1 , wherein the ERβ selective ligand has the Formula IV: 
     
       
         
         
             
             
         
       
     
     wherein:
 R 11  and R 12  are each, independently, selected from hydrogen, hydroxyl, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, and alkynyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, or halogen; 
 R 15 , R 16 , R 17 , R 18 , and R 19  are each, independently, hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, halogen, alkoxy of 1-6 carbon atoms, —CN, —CHO, trifluoromethyl, phenylalkyl of 7-12 carbon atoms, phenyl, or a 5 or 6-membered heterocyclic ring having 1 to 4 heteroatoms selected from O, N or S; wherein the alkyl or alkenyl moieties of R 15 , R 16 , R 17 , R 18 , or R 19  may be optionally substituted with hydroxyl, —CN, halogen, trifluoroalkyl, trifluoroalkoxy, —NO 2 , or phenyl; wherein the phenyl moiety of R 15 , R 16 , R 17 , R 18 , or R 19  may be optionally mono-, di-, or tri-substituted with alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, halogen, hydroxyl, alkoxy of 1-6 carbon atoms, —CN, —NO 2 , amino, alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms per alkyl group, thio, alkylthio of 1-6 carbon atoms, alkylsulfinyl of 1-6 carbon atoms, alkylsulfonyl of 1-6 carbon atoms, alkoxycarbonyl of 2-7 carbon atoms, alkylcarbonyl of 2-7 carbon atoms, or benzoyl; and 
 wherein at least one of R 15  or R 19  is not hydrogen, or a pharmaceutically acceptable salt thereof. 
 
   
   
       18 . The pharmaceutical composition of  claim 17 , wherein the ERβ selective ligand has the Formula V: 
     
       
         
         
             
             
         
       
     
     wherein:
 R 11  and R 12  are each, independently, selected from hydrogen, hydroxyl, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, and alkynyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, or halogen; 
 R 15 , R 16 , R 17 , R 18 , and R 19  are each, independently, hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, halogen, alkoxy of 1-6 carbon atoms, —CN, —CHO, trifluoromethyl, phenylalkyl of 7-12 carbon atoms, phenyl, or a 5 or 6-membered heterocyclic ring having 1 to 4 heteroatoms selected from O, N or S; wherein the alkyl or alkenyl moieties of R 15 , R 16 , R 17 , R 18 , or R 19  may be optionally substituted with hydroxyl, CN, halogen, trifluoroalkyl, trifluoroalkoxy, NO 2 , or phenyl; wherein the phenyl moiety of R 15 , R 16 , R 17 , R 18  or R 9  may be optionally mono-, di-, or tri-substituted with alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, halogen, hydroxyl, alkoxy of 1-6 carbon atoms, CN, —NO 2 , amino, alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms per alkyl group, thio, alkylthio of 1-6 carbon atoms, alkylsulfinyl of 1-6 carbon atoms, alkylsulfonyl of 1-6 carbon atoms, alkoxycarbonyl of 2-7 carbon atoms, alkylcarbonyl of 2-7 carbon atoms, or benzoyl; and 
 wherein at least one of R 15  or R 19  is not hydrogen, or a pharmaceutically acceptable salt thereof. 
 
   
   
       19 . The pharmaceutical composition of  claim 18 , wherein the 5 or 6-membered heterocyclic ring having 1 to 4 heteroatoms selected from O, N or S is furan, thiophene or pyridine, and R 15 , R 16 , R 17 , R 18 , and R 19  are each, independently, hydrogen, halogen, —CN, or alkynyl of 2-7 carbon atoms. 
   
   
       20 . The pharmaceutical composition of  claim 18 , wherein R 16 , R 17 , and R 18  are hydrogen. 
   
   
       21 . The pharmaceutical composition of  claim 2 , wherein the ERβ selective ligand has the Formula IV: 
     
       
         
         
             
             
         
       
     
     wherein:
 R 11  and R 12  are each, independently, selected from hydrogen, hydroxyl, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, and alkynyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, or halogen; 
 R 15 , R 16 , R 17 , R 18 , and R 19  are each, independently, hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, halogen, alkoxy of 1-6 carbon atoms, —CN, —CHO, trifluoromethyl, phenylalkyl of 7-12 carbon atoms, phenyl, or a 5 or 6-membered heterocyclic ring having 1 to 4 heteroatoms selected from O, N or S; wherein the alkyl or alkenyl moieties of R 15 , R 16 , R 17 , R 18 , or R 19  may be optionally substituted with hydroxyl, —CN, halogen, trifluoroalkyl, trifluoroalkoxy, —NO 2 , or phenyl; wherein the phenyl moiety of R 15 , R 16 , R 17 , R 18 , or R 19  may be optionally mono-, di-, or tri-substituted with alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, halogen, hydroxyl, alkoxy of 1-6 carbon atoms, —CN, —NO 2 , amino, alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms per alkyl group, thio, alkylthio of 1-6 carbon atoms, alkylsulfinyl of 1-6 carbon atoms, alkylsulfonyl of 1-6 carbon atoms, alkoxycarbonyl of 2-7 carbon atoms, alkylcarbonyl of 2-7 carbon atoms, or benzoyl; and 
 wherein at least one of R 15  or R 19  is not hydrogen, or a pharmaceutically acceptable salt thereof. 
 
   
   
       22 . The pharmaceutical composition of  claim 1 , wherein the ERβ selective ligand is a compound having the Formula: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof. 
   
   
       23 . The pharmaceutical composition of  claim 22 , wherein the solubilizer/complexant component is selected from the group consisting of hydroxypropyl beta-cyclodextrin and sulfobutyl ether beta-cyclodextrin. 
   
   
       24 . The pharmaceutical composition of  claim 22 , wherein the solubilizer/complexant component comprises hydroxypropyl beta-cyclodextrin. 
   
   
       25 . The pharmaceutical composition of  claim 22 , wherein the pH adjusting component is selected from the group consisting of group I and group II metal hydroxides. 
   
   
       26 . The pharmaceutical composition of  claim 22 , wherein the pH adjusting component is selected from the group consisting of NaOH and KOH. 
   
   
       27 . The pharmaceutical composition of  claim 22 , wherein:
 the solubilizer/complexant component is selected from the group consisting of hydroxypropyl beta-cyclodextrin and sulfobutyl ether beta-cyclodextrin; and   the pH adjusting component is selected from the group consisting of group I and group II metal hydroxides.   
   
   
       28 . The pharmaceutical composition of  claim 27 , wherein the pH adjusting component is selected from the group consisting of NaOH and KOH. 
   
   
       29 . The pharmaceutical composition of  claim 27 , wherein the solubilizer/complexant component is hydroxypropyl beta-cyclodextrin; and the pH adjusting component comprises NaOH. 
   
   
       30 . The pharmaceutical composition of  claim 2 , wherein the ERβ selective ligand is a compound having the Formula: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof. 
   
   
       31 . The pharmaceutical composition of  claim 1 , wherein the solubilizer/complexant component is selected from cyclodextrins and substituted cyclodextrins. 
   
   
       32 . The pharmaceutical composition of  claim 1 , wherein the solubilizer/complexant component is selected from the group consisting of hydroxypropyl beta-cyclodextrin and sulfobutyl ether beta-cyclodextrin. 
   
   
       33 . The pharmaceutical composition of  claim 1 , wherein the solubilizer/complexant component comprises hydroxypropyl beta-cyclodextrin. 
   
   
       34 . The pharmaceutical composition of  claim 1 , wherein the pH adjusting component is selected from the group consisting of group I and group II metal hydroxides. 
   
   
       35 . The pharmaceutical composition of  claim 1 , wherein the pH adjusting component is selected from the group consisting of NaOH and KOH. 
   
   
       36 . The pharmaceutical composition of  claim 1 , wherein:
 the solubilizer/complexant component is selected from the group consisting of hydroxypropyl beta-cyclodextrin and sulfobutyl ether beta-cyclodextrin; and   the pH adjusting component is selected from the group consisting of group I and group II metal hydroxides.   
   
   
       37 . The pharmaceutical composition of  claim 36 , wherein the pH adjusting component is selected from the group consisting of NaOH and KOH. 
   
   
       38 . The pharmaceutical composition of  claim 36 , wherein the solubilizer/complexant component is hydroxypropyl beta-cyclodextrin; and the pH adjusting component comprises NaOH. 
   
   
       39 . The pharmaceutical composition of  claim 36 , wherein the pH adjusting component is selected from the group consisting of NaOH and KOH. 
   
   
       40 . The pharmaceutical composition of  claim 36 , wherein the solubilizer/complexant component is hydroxypropyl beta-cyclodextrin; and the pH adjusting component comprises NaOH. 
   
   
       41 . The pharmaceutical composition of  claim 1 , wherein:
 the solubilizer/complexant component is selected from the group consisting of hydroxypropyl beta-cyclodextrin and sulfobutyl ether beta-cyclodextrin; and   the ERβ selective ligand has the Formula:   
     
       
         
         
             
             
         
       
       or a pharmaceutically acceptable salt thereof; 
     
     or the Formula: 
     
       
         
         
             
             
         
       
       or a pharmaceutically acceptable salt thereof. 
     
   
   
       42 . The pharmaceutical composition of  claim 41 , wherein the solubilizer/complexant component comprises hydroxypropyl beta-cyclodextrin. 
   
   
       43 . The pharmaceutical composition of  claim 42 , wherein the pH adjusting component is selected from the group consisting of group I and group II metal hydroxides. 
   
   
       44 . The pharmaceutical composition of  claim 42 , wherein the pH adjusting component is selected from the group consisting of NaOH and KOH. 
   
   
       45 . The pharmaceutical composition of  claim 42 , wherein the pH adjusting component comprises NaOH. 
   
   
       46 . The pharmaceutical composition of  claim 42 , wherein:
 said ERβ selective ligand is present in an amount of from about 5 mg/mL to about 10 mg/mL; and   said solubilizer/complexant component is present in an amount of from about 5% (w/v) to about 15% (w/v) of the pharmaceutical composition.   
   
   
       47 . The pharmaceutical composition of  claim 42 , wherein:
 said ERβ selective ligand is present in an amount of about 10 mg/mL; and   said solubilizer/complexant component is present in an amount of about 15% (w/v) of the pharmaceutical composition.   
   
   
       48 . The pharmaceutical composition of  claim 1  having a potency of the ERβ selective ligand in said pharmaceutical composition greater than or equal to about 99% at two months at 4° C. 
   
   
       49 . The pharmaceutical composition of  claim 1 , wherein less than or equal to about 0.01% of the ERβ selective ligand precipitates in two minutes after a 1000-fold dilution of said pharmaceutical composition with phosphate buffered saline. 
   
   
       50 . The pharmaceutical composition of  claim 1 , wherein less than or equal to about 0.1% of the ERβ selective ligand precipitates in two minutes after a 1000-fold dilution of said pharmaceutical composition with phosphate buffered saline. 
   
   
       51 . A method for preparing a pharmaceutical composition of  claim 1 , the method comprising:
 (i) providing a container comprising said ERβ selective ligand;   (ii) adding said solubilizer/complexant component to said container to form a first mixture;   (iii) adding sterile water to said container to form a second mixture;   (iv) add said pH adjustment component to said second mixture to form a third mixture;   (v) dissolving the components of said third mixture to form a solution; and   (vi) filtering said solution.   
   
   
       52 . A product of the process of  claim 51 . 
   
   
       53 . A method for treating a subject suffering from arthritis or endometriosis, the method comprising administering to said subject a therapeutically effective amount of a pharmaceutical composition of  claim 1 . 
   
   
       54 . The method of  claim 53 , wherein said solubilizer/complexant component is present in an amount sufficient to reduce the incidence of phlebitis as compared to administration of a therapeutically effective amount of a pharmaceutical composition of  claim 1  which does not comprise said solubilizer/complexant component. 
   
   
       55 . A kit comprising a composition of  claim 1 , and container therefor.